Parkinson's disease (PD) is a chronic neurodegenerative disorder. Although we do not yet understand its cause, there is extensive degeneration of nigro-striatal DA neurons. Powerful neurotrophic factors, which could be used for the treatment of Parkinson's disease, have been described recently. The ultimate goal of this proposal is to develop novel high-capacity adenoviral systems for long term, stable, non-cytotoxic, and non-immunogenic delivery of neuroprotective genes to the brain for both experimental transgene expression in adult animals, and for the future treatment of chronic neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease by gene therapy. Currently used adenoviruses are efficient vectors for gene transfer into the brain. However, their use has been limited by high doses of vectors needed, vector-cytotoxicity, short-term transgene expression, and deleterious effects of anti-adenovirus inflammatory and immune responses. These limitations are due to: (i) low efficiency of transcriptional promoter elements currently used, which directly leads to the need to use higher doses of vectors, and (ii) cytotoxicity and immunogenicity of viral proteins expressed from the genomes of first generation adenoviral vectors. We now wish to initiate the next stage in the design of efficient, safe, long-term expressing vectors for neurological gene therapy. First, high-capacity helper-dependent adenoviral vectors that express no adenoviral genes will be constructed. Second, the amount of protein produced per input virus will be increased by using stronger promoters alone, or combined with enhancer elements. Third, the efficacy of the new vectors will be tested, by expressing selected neuroprotective genes and verify that they are effective in a model of neurodegeneration. The reagents and principles established by this work will be of substantial value to those with interests in the basic and clinical neurosciences, and will lead to the development of novel approaches to the treatment of chronic neurodegenerative diseases. This research will facilitate the development of the tools needed to achieve long-lived, safe, non-cytotoxic transgene expression, and, ultimately, for the treatment of patients suffering from chronic neurodegenerative disorders.